Somatic mutations in single human cardiomyocytes reveal age-associated DNA damage and widespread oxidative genotoxicity
The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide varian...
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Published in | Nature aging Vol. 2; no. 8; pp. 714 - 725 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Nature Publishing Group
01.08.2022
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Subjects | |
Online Access | Get full text |
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Summary: | The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in 56 single cardiomyocytes from 12 individuals (aged from 0.4 to 82 years). Cardiomyocyte sSNVs accumulate with age at rates that are faster than in many dividing cell types and nondividing neurons. Cardiomyocyte sSNVs show distinctive mutational signatures that implicate failed nucleotide excision repair and base excision repair of oxidative DNA damage, and defective mismatch repair. Since age-accumulated sSNVs create many damaging mutations that disrupt gene functions, polyploidization in cardiomyocytes may provide a mechanism of genetic compensation to minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S.C., M.H.C., A.Y.H., E.A.L. and C.A.W. conceived and designed the study. C.A.W., E.A.L. and M.H.C. supervised the study. S.C., A.Y.H., E.A.L., M.H.C. and C.A.W. wrote the article. S.C., Z.Z., K.M., J.W.T., M.B.M., M.A.L., S.A. and N.H. isolated single nuclei and performed whole-genome amplification as well as single-cell WGS. A.Y.H. performed sSNV calling from single-cell WGS data and performed bioinformatics analyses. J.K. performed quality control and read alignment of single-cell WGS data. E.A.M. and A.Y.H. analyzed GTEx expression data and performed knockout cell modeling. All authors reviewed and edited the article. Author contributions |
ISSN: | 2662-8465 2662-8465 |
DOI: | 10.1038/s43587-022-00261-5 |